Nephronophthisis-associated ciliopathy within Sensenbrenner's syndrome: clinical report and literature review

Sensenbrenner syndrome, also known as cranio-ectodermal dysplasia, is an ultrarare autosomal recessive ciliopathy caused by pathogenic variants in one of six genes including IFT43, IFT52, IFT122, IFT140, WDR19, and WDR35, all encoding proteins that are part of the intraflagellar transport complex A which is involved in retrograde ciliary transport. Sensenbrenner syndrome is a multiple anomaly syndrome with distinctive craniofacial findings (forehead bossing, dolichocephaly), metaphyseal dysplasia (short limbs, small thorax), ectodermal anomalies (sparse hair, small and missing teeth, short nails), connective tissue abnormalities (loose skin, joint laxity), retinal dystrophy, and chronic kidney and liver disease. In this article, we present a 5-year-old male patient diagnosed with Sensenbrenner syndrome as a typical craniofacial and skeletal anomaly with kidney disease and progressive decline in kidney function. The boy is the second child of healthy non-consanguineous parents. His birth weight was 3390 g (50‰) and the birth length was 51 cm (50‰). Clinical examination performed directly after birth, revealed craniofacial and skeletal abnormalities (dolichocephaly, wide forehead, epicanthic folds, telecanthus, narrow thorax, short limbs, brachydactyly, syndactyly of 2-3 toes of both feet). Postnatal kidney ultrasound (US) showed normal-sized kidneys without parenchymal changes. At the age of 14 months, the boy underwent a surgical correction for scaphocephaly. At the age of 2 years the child presented with failure to thrive, US revealed bilateral solitary parenchymal cysts (<1 cm) in both kidneys. At the first admission at the age of 4 years, the boy had short stature, lumbar scoliosis, metabolic acidosis, proteinuria up to 1.0 g/l with elevated urinary β-2 microglobulin level and microalbuminuria, decreased calcium excretion, increased fractional excretion of potassium, sodium, and magnesium. His eGFR was decreased to 54.7 ml/min/1.73 m2. Kidney US revealed a few cysts (RK 1.3×1.6 cm, LK 0.8×0.6 cm) and single medullary calcifications in both kidneys. Oral sodium hydrocarbonate was given to the patient to correct metabolic acidosis. Treatment with ACE inhibitor (iACE) (enalapril, 0.125 mg/kg/d) was started for antiproteinuric and nephroprotective purposes. NGS identified a variant of uncertain significance с.2907G>T (p.Lys969Asn) in exon 25 of the WDR35 gene in a homozygous state. Both parents were found to be heterozygous carriers of this WDR35 variant. 12-month therapy with sodium bicarbonate led to normalization of the acid-base state, and treatment with iACE led to decreasing proteinuria, microalbuminuria, and stabilization of his kidney function (eGFR 50.1 ml/min/1.73 m2).

краниоэктодермальная дисплазия, цилиопатия, скафоцефалия, нефронофтиз, почечная недостаточность, cranio-ectodermal dysplasia, ciliopathy, scaphocephaly, nephronophthisis, renal failure

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